Drug addiction is associated with persistent alterations in behavior and neurochemistry. This project seeks to identify the behavioral consequences of repeated psychostimulant and opiate use and the neuroadaptations within the brain which underlie their development and long term expression. Previously, we showed that dopamine(DA) uptake and release within the nucleus accumbens are increased during abstinence from cocaine. These changes in DA dynamics are thought to underlie the enhanced behavioral responses to cocaine (e.g. sensitization) which occur in experimental animals previously exposed to this agent. Our work has shown that the systemic administration of k-opioid receptor agonists prevents these changes. In animals which have received a k-opioid receptor agonist in combination with cocaine, increases in uptake and release which occur during abstinence are no longer seen. These animals also fail to exhibit sensitization to the psychomotor stimulant effect of cocaine and reinstatement of cocaine- seeking behavior. Such treatment also prevents the enhancement of cocaine-evoked DA overflow within the nucleus accumbens which occur weeks after the discontinuation of drug use. Mapping studies have shown that the activation of k-opioid receptors in the nucleus accumbens produces these same effects. They prevent cocaine-induced behavioral sensitization and also attenuate cocaine-induced alterations in DA neurochemistry. In contrast, the selective blockade of k-opioid receptors in this brain region exacerbates the behavioral and neurochemical effects associated with repeated cocaine use. The effects of k-opioid agonists infused into the prefrontal cortex and ventral pallidum are identical to those observed following the blockade of k- receptors in the nucleus accumbens. An augmentation of the behavioral and neurochemical effects of cocaine are seen. In contrast, activation of k-opioid receptors in other brain regions (e.g. basolateral amygdala, dorsal striatum) are without effect. These data indicate brain region specific interactions of k-opioid receptor systems with cocaine. In vitro studies suggest an involvement of the DA transporter and the excitatory amino acid, glutamate, in mediating the cocaine antagonist-like effects of cocaine. Our recent studies have shown that k-agonist administration antagonizes the psychomotor stimulant effects of acutely administered amphetamine and antagonizes increases in DA and glutamate release which occur in response to the administration of this psychostimulant. Dialysis and transporter binding studies have revealed that k-agonist administration also attenuates the neurotoxic effects of methamphetamine on mesostriatal DA neurons. Dialysis studies in genetically manipulated mice have been initiated in order to identify the role of k-opioid receptors as well as other neurotransmitter systems and receptors(serotonin-1a and 1b; D3-DA) in modulating DA neurotransmission and individual differences in responsiveness to drugs of abuse. Finally, in vitro and in vivo techniques are being used to identify the role of phosphorylation and receptor internalization in mediating the above interactions. - neuroadaptations, neurochemistry, drug addiction, cocaine, opiates, opioid peptides